Women have a more difficult time quitting smoking than men and face more significant specific gender-related health consequences from smoking. Several factors could undermine smoking cessation in women, including depressive symptoms and menstrual phase. Studies have explored the impact of major depression on smoking cessation, but few have examined the effects of lesser depressive symptoms which are experienced by a significant portion of female smokers who may require targeted interventions. Compounding the depression-related difficulty in quitting smoking are the lifetime hormonal fluctuations that also affect mood, i.e. menstrual phase sex hormones. This 4-year competing renewal application is an extensive and systematic experimental study of women smokers (N=200) to determine the effect of depressive symptoms, alone and in concert with ovarian hormones (menstrual phase - follicular/mid-luteal), on withdrawal symptoms, nicotine craving, smoking urges, premenstrual symptoms and cortisol levels (stress response) during acute smoking abstinence. The second aim is to determine if depressive symptoms and menstrual phase moderate nicotine response on recognized response systems (physiological, subjective, behavioral, pharmacokinetics and neuroendocrine) following acute smoking abstinence. The study will include a within-subject factor (follicular vs. mid-luteal phase) and a between-subjects factor (nondepressed and subclinical depressed women smokers) where subjects will be asked to abstain from smoking for 4 days following 2 days of ad lib smoking during alternate cycle phases. On the 4th day of abstinence nicotine response will be measured using metered doses of nicotine nasal spray. Results from this study will be invaluable to gain further insight into whether and how depressive symptoms and cycle phase affect smoking cessation attempts. This information will guide the development of tailored treatments and provide evidence-based guidelines for clinicians with the ultimate long term goal of reducing smoking related harms in women.